Journal
NEUROBIOLOGY OF AGING
Volume 35, Issue 5, Pages 1002-1011Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2013.10.090
Keywords
Aging; Alzheimer's disease; Calcium; T-type calcium channel; APP processing; Amyloid; Calpains
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Funding
- Alzheimer's Association
- American Federation for Aging Research
- NIH [AG00538]
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Alzheimer's is a crippling neurodegenerative disease that largely affects aged individuals. Decades of research have highlighted age-related changes in calcium homeostasis that occur before and throughout the duration of the disease, and the contributions of such dysregulation to Alzheimer's disease pathogenesis. We report an age-related decrease in expression of the CaV3.1 T-type calcium channel at the level of messenger RNA and protein in both humans and mice that is exacerbated with the presence of Alzheimer's disease. Downregulating T-type calcium channels in N2a cells and the 3xTg-AD mouse model of Alzheimer's disease, by way of pharmacologic inhibition with NNC-55-0396, results in a rapid increase in amyloid beta production via reductions in non-amyloidogenic processing, whereas genetic overexpression of the channel in human embryonic kidney cells expressing amyloid precursor protein produces complementary effects. The age-related decline in CaV3.1 expression may therefore contribute to a pro-amyloidogenic environment in the aging brain and represents a novel opportunity to intervene in the course of Alzheimer's disease pathogenesis. (C) 2014 Elsevier Inc. All rights reserved.
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